Selective Actinide-Catalyzed Tandem Proton-Transfer Esterification of Aldehydes with Alcohols for the Production of Asymmetric Esters

Article abstract of DOI:10.1021/acs.organomet.7b00101

Actinide-catalyzed tandem proton-transfer esterification between aldehydes and alcohols is presented herein for the first time. It represents a novel convenient and external-oxidant-free methodology in the preparation of asymmetric ester compounds. Various kinds of aldehydes and alcohols can be applied to this reaction, affording the corresponding ester product in moderate to high yields. A plausible mechanism was proposed on the basis of the kinetic, stoichiometric, and deuterium-labeling studies.

Full text of DOI:10.1021/acs.organomet.7b00101

Communication
pubs.acs.org/Organometallics
Selective Actinide-Catalyzed Tandem Proton-Transfer Esterification
of Aldehydes with Alcohols for the Production of Asymmetric Esters
Heng Liu and Moris S. Eisen*
Schulich Faculty of Chemistry, Technion−Israel Institute of Technology, Haifa City 32000, Israel
*
S Supporting Information
ABSTRACT: Actinide-catalyzed tandem proton-transfer esterification between
aldehydes and alcohols is presented herein for the first time. It represents a novel
convenient and external-oxidant-free methodology in the preparation of asymmetric
ester compounds. Various kinds of aldehydes and alcohols can be applied to this
reaction, affording the corresponding ester product in moderate to high yields. A
plausible mechanism was proposed on the basis of the kinetic, stoichiometric, and
deuterium-labeling studies.
xploring new esterification strategies is a very challenging
endeavor in modern synthetic chemistry. In addition to
to complete the cycle (vide infra). On the basis of these
E
consideration, a series of direct esterification studies between
aldehydes and alcohols is disclosed herein by using the
metallacyclic actinide amido complexes [(Me Si) N] An-
being routinely obtained from nucleophilic substitution reactions
between carboxylic acids and alcohols, esters can also be
prepared by other methodologies, such as oxidative esterifica-
3
2
2
2
[κ (N,C)-CH Si(CH ) N(SiMe )] (An = Th (1), U (2)) and
2
3 2
3
1
−7
8−12
tion,
the Tishchenko reaction,
dehydrogenative cou-
U[N(SiMe ) ] (3) as precatalysts.
3 2 3
1
3−15
pling,
etc., in which aldehydes are employed as an
To our pleasure, the asymmetric esterification process can be
smoothly catalyzed by actinide complexes 1−3 to generate the
corresponding esters, despite the high bond energies of
alternative to carboxylic acids. However, challenges remain in
these processes. For example, the Tishchenko reaction is not
16,17
4
1
adequate for the synthesis of unsymmetrical esters
and in the
actinide−oxygen bonds, and representative results are
summarized in Table 1. Initial optimization investigations
using benzaldehyde and methanol substrates revealed that the
thorium(IV) amido complex 1 performed with the best activities
among the three precatalysts. Catalytic reactions using the U(IV)
oxidative esterification, an external oxidant is indispensable,
which will potentially oxidize alcohols to aldehydes and afterward
result in selectivity-controlling issues and byproduct formation.
Therefore, developing a more convenient external-oxidant-free
esterification methodology, which is also capable of giving rise to
unsymmetrical esters, is highly demanding.
(
2) and U(III) (3) complexes gave lower yields of the
corresponding ester. Increasing the amount of PhCHO
enhanced the yield of the methyl benzoate 6aa significantly; up
to 73% conversion was obtained with a 3:1 molar ratio (the initial
The past few decades have witnessed tremendous advances in
18−27
the design and application of organoactinide catalysts.
In
the forefront of research is the catalytic transformation of
oxygenated substrates, due to the high oxophilicity of the
actinides, forming thermodynamically stable actinide−oxo
−1
TOF value is up to 1.25 h ), implying that a high concentration
of aldehydes is a crucial factor in achieving the desired
transformation. However, increasing the MeOH amount to 3
equiv displayed a negative effect on the ester yield, with only 6%
MeOH consumption based on alcohol (42% yield based on
aldehyde). Performing the reaction in toluene-d or benzene-d
afforded comparable conversions, whereas in THF-d, some
inhibition is observed.
26,28,29
species in the presence of oxygen-containing compounds.
To date, a very limited number of processes involve oxygen-
3
0,31
containing substrates, such as hydroalkoxylation,
the
32−34
35
Tishchenko reaction,
ester polymerization,
small-molecule activation, cyclic
and the catalytic formation of
3
6−38
3
9
hydrogen from water. We have recently disclosed that
imidazolin-2-iminato actinide precursors are able to react with
Once the optimized conditions were established, our attention
turned to an investigation of the scope capabilities and
limitations. A wide variety of combinations of substrates was
investigated, and the results are shown in Table 1. We observe
that activated benzaldehydes with electron-withdrawing groups,
such as 4-Cl, 4-NO , 3-NO , 4-CN, and 4-CF , displayed
an aldehyde, R CHO, generating the actinide alkoxide moieties
2
An-OCH R , able to serve as an effective active species to afford
2
2
40
the corresponding symmetric esters. Inspired by that work, we
envisage that, if the actinide precursor is able to undergo first a
30,31
2
2
3
rapid alcoholysis in the presence of alcohols R OH,
the
1
activities higher than that of benzaldehyde even at shorter times,
which is the result of the relatively easier hydride transfer from
the 2° carbon of the hemiacetalate to the carbonyl of the
resulting analogous actinide alkoxide species, An-OR , could also
1
react with an aldehyde to furnish the asymmetric ester
compound R COOR selectively. Moreover, it is of note that
2
1
the actinide alkoxide species, generated from the esterification
cycle, is different from that produced from the alcoholysis step;
therefore, an additional proton-transfer step is required in order
Received: February 8, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00101
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Organometallics
Communication
Table 1. Catalysis of the Asymmetric Esterification of
Aldehydes with Alcohols by Complexes 1−3
containing substrates to the thorium center. Steric hindrance of
the aldehyde also plays an important role in determining the
reactivities. Reacting 1-naphthaldehyde with MeOH afforded
less conversion in comparison with benzaldehyde, and a further
increase in the steric encumbrance by using 9-anthrylaldehyde
resulted in a completely inhibited reactivity, with no ester
production after 24 h. In striking contrast, the reaction of 2-
naphthaldehyde with MeOH gave rise to ester yields comparable
to that with benzaldehyde, indicating that substituents on the
ortho position of benzaldehyde suppressed the reactivity
significantly. A similar result was obtained when 2-methyl-
benzyldehyde was reacted with MeOH, giving rise to ester 6na in
a
1
3% yield, which is much lower than the value obtained for its
isomer 6ga. Aliphatic aldehydes, including phenylacetaldehyde,
cyclohexanecarboxaldehyde, and isobutyraldehyde, were also
used to couple with MeOH; however, only the symmetric esters
were obtained. In addition to methanol, ethanol, benzyl alcohol,
and isopropyl alcohol were also applied in this reaction, but
unfortunately, all of them lead to relatively lower ester yields in
comparison with MeOH, even when using activated 3-nitro-
benzaldehyde was used. The reaction of the tertiary alcohol
t
BuOH with aldehydes gave no products, implying that the steric
encumbrance of the alcohol, with similar aldehydes, also has a
great influence on the efficiency of the catalytic system.
During this esterification process, two kinds of byproducts, i.e.,
substituted benzyl alcohols and symmetrically coupled esters,
were detected, which were generated from the proton-transfer
step and the Tishchenko cycle, respectively. Monitoring the
1
progress of the reaction of PhCHO/MeOH system using H
NMR spectroscopy showed that the benzyl alcohol was formed
concurrently with 6aa from the beginning of the reaction with a
roughly 1:1 ratio. This result corroborates the proton-transfer
step; while benzyl benzoate was not observed until a majority of
MeOH was consumed, then the Tishchenko cycle turned into
the predominant catalytic cycle. These observations rule out the
possibility of a transesterification reaction between actinide
methoxides and symmetrical benzyl benzoate to form the
unsymmetrical ester product 6aa. It is noteworthy that increasing
the concentration of the alcohols will induce lower ester yields;
however, it will also suppress the Tishchenko reaction
completely and will generate compound 6aa as the only product,
manifesting a selective method in preparing unsymmetrical
esters. Another strategy of suppressing the Tishchenko cycle was
inspired by the rate discrepancy between secondary alcohols and
methanol. We assume that if one special kind of ketone could
participate and act as a good hydride acceptor during the six-
membered-ring transition state, the produced secondary alcohols
will have sluggish activities in comparison to methanol, and
hence a majority of the reduced secondary alcohol will be left
unreacted in the reaction medium. As a study case, the ketone
α,α,α-trifluoromethylacetophenone (TFMAP) was chosen as a
hydride acceptor, since the presence of the phenyl ring will
increase the steric hindrance of the resulted secondary alcohol,
inducing reduced reactivity, and the presence of the trifluor-
omethyl group will allow rapid approach of a hydride to its
carbonyl moiety at the six-membered transition state (Scheme
1). With this hypothesis, a sacrificial proton transfer esterification
between various kinds of aldehydes and methanol, in the
presence of TFMAP, was conducted, and the representative
results are summarized in Table 2. Table 2 shows that adding 1
equiv of TFMAP to the PhCHO/MeOH mixture efficiently
suppresses the Tishchenko reaction, producing only 3% of the
homocoupled ester after 24 h. Using 1 equiv more of TFMAP
a
Conditions unless specified otherwise: 5.0 mg of precatalyst 1, [1]/
[
CHO]/[OH] = 1/150/50, 700 μL of C D , 70 °C, 24 h. The yield
6 6
1
was determined by H NMR spectroscopy of the crude reaction
b
mixture on the basis of the alcohols. Different precatalysts were used.
c
d
The yield was determined on the basis of the aldehyde. Reaction
e
time 6 h. Reaction at 110 °C in toluene-d.
incoming substrate in a six-membered transition fashion (vide
infra). In contrast, incorporation of electron-donating groups
reduced the ester yields dramatically, displaying values of 55%
and 6% for 4-methyl- and 4-methoxylbenzaldehyde, respectively.
Elevating the temperature to 110 °C showed negligible
improvement in the ester productivities for 4-methoxylbenzal-
dehyde, indicative of an inherent sluggish reactivity caused by
strongly electron donating substituents. For aldehyde substrates
bearing heteroaromatic rings, the corresponding yields were
found to be highly dependent on the nature of heteroatoms, with
the best performance observed in picolinaldehyde, affording a
yield (75%) comparable to that with benzaldehyde. For the other
two substrates, furfural and 2-thenaldehyde, much lower
conversions were obtained. These results presumably are due
to the relatively stronger bidentate binding of sulfur- and oxygen-
B
DOI: 10.1021/acs.organomet.7b00101
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Organometallics
Communication
Scheme 1. Mechanical Procedure of Hydride Transfer Using
TFMAP as Acceptor
Scheme 2. Proposed Mechanism for Tandem Proton-Transfer
Esterification
resulted in a complete shutoff of the Tishchenko cycle, causing
the reaction to proceed selectively through the proton-transfer
esterification cycle and furnishing the asymmetrical ester as the
sole product. Similar results were observed for 4-methylbenzal-
dehyde and 2-naphthaldehyde, indicating a large scope capability
of the sacrificial ketone. During these studies, no cross-coupling
products between aldehyde and TFMAP were detected.
To shed light on the mechanism, an in situ stoichiometric
reaction between precatalyst 1 and 10 equiv of MeOH was first
investigated, which led to the immediate formation of thorium
methoxide species and complete displacement of the amino
groups simultaneously, indicated by the disappearance of the
original amido groups and the appearance of free amine
hexamethyldisilazane HN(SiMe ) signals. To this reaction
3
2
mixture was added 10 equiv of PhCHO, and the corresponding
ester product 6aa was observed. In contrast, the reaction of the
precatalyst 1 with 10 equiv of PhCHO instantly gave rise to the
symmetrical ester product benzyl benzoate and the N(SiMe ) α-
substituted ester, both of which were not observed in the
beginning of the catalytic process, demonstrating that meth-
anolysis of 1 is the first rapid step during the catalytic cycle.
Kinetic studies using PhCHO, methanol, and complex 1
revealed first-order dependence on the precatalyst and aldehyde
and an inverse first-order kinetics in alcohols, giving rise to the
rate equation (1). The inverse first order in alcohols indicates the
MeOH/1 system, revealing a primary kinetic isotope effect
(kPhCHO/kPhCDO = 4.61), which indicates that the hydride transfer
from the hemiacetal intermediate to a coordinated aldehyde,
during the six-membered transition state, is the rate-determining
step. This rationalization is consistent with previous exper-
imental results that using different aldehydes had a great
3
2
4
2
influence on the reactivities. In contrast, a KIE (kMeOH/kMeOD
)
value of 1.04 was obtained when using methanol-d for the
(MeOD)/PhCHO/1 catalytic system, suggesting rapid alcohol-
ysis and proton transfer steps during the catalytic cycle. The
isolation of benzyl alcohol-d and benzyl benzoate-d during
2
2
possibility of excess R OH coordinating to the active species A
these studies again corroborated the proton transfer step.
On the basis of the above analysis, a plausible mechanism for
the proton transfer esterification is presented in Scheme 2. In the
first step, fast acid−base protonolysis of the actinide amido
complexes, by the alcohol, gave rise to the actinide alkoxide
1
(
Scheme 2) and subsequent formation of the deactivated species
E, which implies kinetic inhibition competing with the turnover-
limiting step (a detailed analysis of the kinetic equation can be
43,44
found in the Supporting Information).
44
species A, which then inserted into the carbonyl group of an
aldehyde, affording the actinide species B. In the presence of an
additional 1 equiv of an aldehyde, hydride transfer from
intermediate B to the carbonyl group of the incoming aldehyde,
via a six-membered transition state, is operative, furnishing the
unsymmetrical ester and concomitantly generating the actinide
alkoxide species D. In the presence of excess alcohol, proton
transfer takes place between D and the alcohol, regenerating the
initial active species A and simultaneously releasing 1 equiv of the
substituted benzyl alcohol. Upon consumption of the alcohol, at
∂
∂
p
t
−
1
=
k′[1][R CHO][R OH]
2
1
(1)
Thermodynamic activation parameters were experimentally
calculated from the Eyring and Arrhenius plots, displaying a
moderate activation barrier (E ) of 17.0(0) kcal mol . The
−1
a
⧧
⧧
enthalpy (ΔH ) and entropy (ΔS ) of activation are 16.3(6) kcal
−
1
mol and −26.2(1) eu, respectively, the latter of which being
evocative of an organized transition state. Deuterium labeling
experiments were performed using a benzaldehyde-d (PhCDO)/
a
Table 2. Proton Transfer Esterification in the Presence of the Sacrificial Ketone TFMAP
b
c
entry
[R CHO]
1
[R OH]
2
PhCOCF /MeOH
yield of R COOR (%)
yield of R COOCH R (%)
1 2 1
3
1
2
1
2
3
4
5
6
7
PhCHO
MeOH
MeOH
MeOH
EtOH
1/1
2/1
1/1
2/1
1/1
2/1
1/1
71
68
47
28
65
43
20
3
4-MePhCHO
2-naphthaldehyde
PhCHO
2
3
a
b
1
Conditions: 5 mg of catalyst, [1]/[CHO]/[OH] = 1/150/50, 700 μL of C D , 70 °C, 24 h. Yield was determined by H NMR spectroscopy of the
6
6
c
crude reaction mixture based on MeOH. Yield was based on aldehyde.
C
DOI: 10.1021/acs.organomet.7b00101
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Organometallics
Communication
a later stage of the reaction, the proton transfer step slows down,
and the actinide alkoxide species D will start the Tishchenko
reaction cycle, affording the homocoupled ester. In the presence
of the sacrificial ketone TFMAP, because of its preferable affinity,
TFMAP will outcompete with aldehydes during the coordination
step to the actinide species B, and subsequent hydride transfer
will give rise to α-(trifluoromethyl)benzyl alcoholate actinide
compounds, which then undergo proton transfer with alcohols to
furnish back the active species A (Scheme 1).
In summary, we have demonstrated the ability of organo-
actinides to undergo a tandem proton-transfer esterification.
This reaction can be applied to various combinations of
aldehydes and alcohols. The steric and electronic properties of
these two substrates play a crucial role in determining the
efficiency of the catalysts. In the presence of the sacrificial ketone
α,α,α-trifluoromethylacetophenone, homocoupled symmetrical
ester byproducts can be prevented, giving rise exclusively to
unsymmetrical esters.
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ASSOCIATED CONTENT
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Experimental details, characterization data, kinetic rate
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AUTHOR INFORMATION
■
(33) Sharma, M.; Andrea, T.; Brookes, N. J.; Yates, B. F.; Eisen, M. S. J.
Corresponding Author
Am. Chem. Soc. 2011, 133, 1341−1356.
34) Karmel, I. S. R.; Fridman, N.; Tamm, M.; Eisen, M. S.
Organometallics 2015, 34, 2933−2942.
35) Gardner, B. M.; Stewart, J. C.; Davis, A. L.; McMaster, J.; Lewis,
(
*M.S.E.: e-mail, chmoris@tx.technion.ac.il; tel, +972-4-8292680.
ORCID
(
Moris S. Eisen: 0000-0001-8915-0256
Notes
The authors declare no competing financial interest.
W.; Blake, A. J.; Liddle, S. T. Proc. Natl. Acad. Sci. U. S. A. 2012, 109,
9265−9270.
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4, 636−643.
37) Karmel, I. S. R.; Khononov, M.; Tamm, M.; Eisen, M. S. Catal. Sci.
Technol. 2015, 5, 5110−5119.
38) Hayes, C. E.; Sarazin, Y.; Katz, M. J.; Carpentier, J.-F.; Leznoff, D.
(
ACKNOWLEDGMENTS
■
This work was supported by the Israel Science Foundation
administered by the Israel Academy of Science and Humanities
under Contract No. 78/14 and by the PAZY Foundation Fund
(
B. Organometallics 2013, 32, 1183−1192.
(39) Fox, A. R.; Bart, S. C.; Meyer, K.; Cummins, C. C. Nature 2008,
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(
2015) administered by the Israel Atomic Energy Commission.
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40) Karmel, I. S. R.; Fridman, N.; Tamm, M.; Eisen, M. S. J. Am. Chem.
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41) Haynes, W. M. CRC Handbook of Chemistry and Physics, 96th ed.;
CRC Press: Boca Raton, FL, 2015−2016; pp 9−69.
42) In the actinide amido complex mediated Tishchenko reactions, an
N(SiMe ) α-substituted ester compound was formed in the beginning
H.L. thanks the Technion-Guangdong Fellowship Program.
(
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DOI: 10.1021/acs.organomet.7b00101
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